Although close to 85% of residents in long-term care facilities (LTC) have osteoporosis and the risk of osteoporotic fractures is nearly 10 times that o community dwelling elderly, few are treated and studies are scarce. The large pivotal osteoporosis trials in postmenopausal women exclude those who are sedentary, frail or functionally impaired even though this is the group at highest risk. The potentially potent therapies for osteoporosis in the young may have more risks than benefits in fragile elderly. Furthermore, there are limited data in men. Even though fracture reduction studies are desperately needed, these trials are large, long, and resource intense. Before a fracture reduction study can be justified in this cohort, an investigation demonstrating efficacy and predictability is a necessary first step. We will test the hypotheses that in frail institutionalizd men and women, semiannual subcutaneous denosumab will 1) be efficacious as demonstrated by improvements or preservation in conventional bone density measurements, 2) improve novel measures of trabecular microstructure, and 3) allow us to characterize likely responders. To address these hypotheses, we propose to conduct a 2-year, randomized, double-blind, calcium-vitamin D controlled trial to test the efficacy and predictability of response of the antiresorptiv RANK ligand inhibitor, denosumab, among a cohort of 200 institutionalized frail (gait speed <0.8 m/sec) men and women ? 65 years old. This semiannual subcutaneous therapy negates concerns regarding poor oral absorption or compliance. Use of a non-bisphosphonate avoids the IV-associated acute phase reaction or renal insufficiency contraindications common in this cohort. Assessments will be performed in a mobile lab and will include conventional bone density of the spine and hip, trabecular bone score, markers of bone turnover, fractures, functional status, mobility and safety. Innovative features include 1) the neglected LTC population, 2) inclusion of men, 3) assessment of trabecular microstructure, 4) point of care vertebral fracture images, 5) mobile lab for onsite, state-of-the-art assessments and 6) an electronic alert system to collect real time serious adverse events including potential denosumab associated adverse events of infection or hypocalcemia. Eight LTC facilities in the Pittsburgh area have agreed to participate. We have the unique advantage of building on our established LTC infrastructure and track record. Regardless of outcome, critical public health knowledge will be gained. This study will provide the necessary data on the efficacy and predictability of response to osteoporosis treatment in LTC residents and will lay the foundation for future effectiveness studies.